This woman's breast cancer treatment caused an extreme case of arm lymphedema.

VOISIN/SCIENCE SOURCE

New therapies could treat tissue swelling that afflicts cancer surgery patients and others

Every night for the past 5 years, Patricia Egan has prepared for bed by pulling on a pair of chipped foam leggings that encase her limbs from her toes to the tops of her thighs. The custommade garments, which look like something a hockey goalie might wear, are supposed to prevent her legs from swelling. But they also make her feel claustrophobic and keep her awake, says Egan, 67, a retired writer from Chico, California. In the morning, she switches to less cumbersome toe gloves and knee-high compression socks that can still be uncomfortable.

Egan needs this bothersome and costly clothing because she suffers from lymphedema, a condition in which the fluid known as lymph doesn't drain normally from a limb or other part of the body. Many cases of lymphedema result from surgery for breast cancer and other tumors that severs the lymphatic vessels, which transport lymph and immune cells, but Egan's is a rare inherited form. "It's like being 8 months pregnant all the time," she says. "Your legs feel swollen and heavy, and they just won't move." As the lymph pools, it can also cause a host of other health problems.

Although Egan's compression clothing curtails swelling, it can't reestablish her lymphatic circulation—no U.S. Food and Drug Administration–approved therapy can. That's why she recently jumped at the chance to participate in a clinical trial at Stanford University School of Medicine in Palo Alto, California. Researchers there and at several other institutions were testing whether the drug ubenimex, a leukemia treatment used in Japan, can spur the growth of new lymphatic vessels.

Results of this phase II trial may be announced later this year, and researchers have started or are planning trials of other strategies for regenerating lymphatic vessels. If the treatments work, they could benefit many of the 5 million to 6 million people in the United States—and more than 100 million around the world—with lymphedema. Improved lymph flow could also help in conditions other than lymphedema. Recent studies have implicated poor lymphatic drainage in glaucoma, rheumatoid arthritis, atherosclerosis, Alzheimer's disease, and other illnesses.

That lymphedema might be curable "was unthinkable a few years ago," says developmental biologist Guillermo Oliver of Northwestern University Feinberg School of Medicine in Chicago, Illinois. The new hope reflects growing knowledge about the lymphatic system. "We are starting to understand much better the molecular principles of how lymphatic vessels work," says vascular biologist Tatiana Petrova of the University of Lausanne in Switzerland. Researchers are also uncovering some of the molecules and cells that prevent lymphatic vessels from repairing themselves after they are damaged by cancer surgery, radiation treatment, or, in the developing world, parasite infections.

Lymphedema "starts out as a plumbing problem," says Stanford cardiologist Stanley Rockson, who first diagnosed Egan's lymphedema and is one of the researchers who ran the recent ubenimex trial. But over time, the uncleared lymph leads to "pretty profound changes in the structure of the affected part of the body," he says. One consequence is fibrosis—the proliferation of connective tissue—that can stiffen and thicken the skin. Fat cells proliferate, too, adding to the swelling.

The lymphatic system starts to grow before birth and is fully formed by soon afterward. However, adults can produce new lymphatic vessels, a process termed lymphangiogenesis, after injuries. The drug Rockson's group is studying blocks a lipid molecule, known as leukotriene B4, that curbs this regrowth. As Rockson and his colleagues reported last year in Science Translational Medicine, lymphedema patients have high levels of the molecule. The scientists also found that low concentrations of the molecule induce new lymphatic vessels to sprout. Ubenimex knocks leukotriene B4's concentration down to the progrowth range. "It unlocks the potential of the lymphatic vessels to repair themselves," says Rockson, who has no financial connection to the drug's manufacturer.

The biotech company Herantis Pharma in Espoo, Finland, is testing a more radical approach, gene therapy, to stimulate lymph vessel regeneration in women who developed arm lymphedema after lymph nodes in the armpit were removed during breast cancer surgery. During this treatment, patients undergo a second operation to replace the excised lymph nodes with nodes taken from elsewhere in their body. Although this transfer alone can combat lymphedema, it's unsuitable for many patients and others don't want to risk surgery. The Herantis approach aims to boost the effectiveness of the transfer and involves injecting the lymph nodes with a cold virus that carries the gene for the growth factor VEGF-C, which stimulates lymphangiogenesis. The immune system quickly eliminates the virus after the nodes are in place, notes the company's CEO, Pekka Simula, but its cargo will spur production of VEGF-C for about 2 weeks.

Babak Mehrara, a reconstructive plastic surgeon at Memorial Sloan Kettering Cancer Center in New York City who treats lymphedema patients, questions the therapy's rationale. Sluggish lymphangiogenesis does not result from a shortage of the growth factor, he says. "Patients with lymphedema have tons of VEGF-C, but it's not generating functional lymphatic vessels." And because VEGF-C can promote tumor growth, he's wary of boosting its levels in patients recovering from cancer.

Simula counters that the treatment stimulates a pulse of VEGF-C that is unlikely to spark tumor growth. VEGF-C production is "local, transient, and highly specific to lymphangiogenesis," he says. Earlier this year, Herantis announced that the treatment appeared to be safe in a small trial that involved 15 patients, but it has yet to publish those findings. In June, the company started a phase II trial that will assess the approach's effectiveness in 40 women, who will receive either injections of the virus or a placebo shot.

Mehrara and his colleagues have followed a different strategy that capitalizes on recent findings about the immune system's role in lymphedema. "We have a very good understanding of the pathways of lymphedema, much better than we did 10 to 15 years ago," he says. One pathway involves the immune cells known as Th2 cells. As Mehrara's team has discovered over the past 5 years, these cells accrue after damage to lymphatic vessels. They swarm into the skin and pump out chemical signals called cytokines that curtail lymphangiogenesis and promote fibrosis. The researchers started a phase II trial of two antibodies that neutralize these cytokines but had to halt it when the drugs' manufacturer discontinued them. Now, they are planning a new trial using a different drug.

All three lymphedema approaches face significant hurdles. Even if a treatment does improve a patient's lymph flow, for instance, "the skin will still be fibrous and elephantlike, and the fat is still there" says physiologist Joseph Rutkowski of the Texas A&M College of Medicine in College Station. Flushing the excess lymph may eventually reverse fibrosis and fat accumulation, he says, but "we haven't had the means" to test it. Another issue is whether any successful treatment will be affordable for the millions of lymphedema patients in developing countries.

But in the Stanford trial, Egan, who has become a patient activist, says she has seen "the most remarkable improvement" in her lymphedema. She is certain she received the active compound rather than the placebo. "One morning I woke up and I could see an ankle bone, I could see a shin bone. I could see definition in my legs I hadn't seen in decades." The swelling in her legs has gone down so much, she says, that the leggings she wore at night were no longer snug. She is swapping them for a smaller, cheaper version that only covers her lower legs.